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Ariel E Feldstein - One of the best experts on this subject based on the ideXlab platform.
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limited value of plasma Cytokeratin 18 as a biomarker for nash and fibrosis in patients with non alcoholic fatty liver disease
Journal of Hepatology, 2014Co-Authors: Kenneth Cusi, Zhi Chang, Steve Harrison, Romina Lomonaco, Fernando Bril, Beverly Orsak, Carolina Ortizlopez, Joan Hecht, Ariel E FeldsteinAbstract:Background & Aims Liver biopsy is the only reliable way of diagnosing and staging NASH but its invasive nature limits its use. Plasma caspase-generated Cytokeratin-18 fragments (CK-18) have been proposed as a non-invasive alternative. We studied its clinical value in a large multiethnic NAFLD population and examined its relationship to clinical/metabolic/histological parameters. Methods 424 middle-aged subjects in whom we measured adipose tissue, liver and muscle insulin resistance (IR), liver fat by MRS (n=275) and histology (n=318). Results Median CK-18 were elevated in patients with vs. without NAFLD by MRS (209 [IQR: 137–329] vs. 122 [IQR: 98–155]U/L) or with vs. without NASH (232 [IQR: 151–387] vs. 170 [IQR: 135–234]U/L, both p p p p Conclusions Plasma CK-18 has a high specificity for NAFLD and fibrosis, but its limited sensitivity makes it inadequate as a screening test for staging NASH. Whether combined as a diagnostic panel with other biomarkers or clinical/laboratory tests may prove useful requires further study.
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Cytokeratin 18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis a multicenter validation study
Hepatology, 2009Co-Authors: Ariel E Feldstein, Anna Wieckowska, Rocio A Lopez, Nizar N Zein, Arthur J McculloughAbstract:Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in both children and adults and threatens to become a serious public health problem (1, 2). Indeed, estimates show than about 80 million Americans may have a fatty liver. NAFLD encompasses a wide spectrum of conditions associated with over-accumulation of fat in the liver ranging from nonalcoholic fatty liver (NAFL) or simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis (3). Although NAFL typically follows a benign non-progressive clinical course, NASH is a potentially serious condition, since as many as 25% of patients may progress to cirrhosis and experience complications of portal hypertension, liver failure and hepatocellular carcinoma (4-6). At present, the available non-invasive tests to distinguish NASH from NAFL include clinical signs and symptoms, routine laboratory and radiological imaging tests and combinations of clinical and blood test results (7). Unfortunately, these tests are of limited utility, and liver biopsy remains the only reliable way of diagnosing NASH and grading the severity of liver damage. However, it is obvious that an invasive liver biopsy is poorly suited as a diagnostic test in such a prevalent condition. There is, therefore, an urgent need to develop and validate a simple, reproducible, non-invasive test that both accurately distinguishes NASH from NAFL and determines the stage and grade of the disease. Several investigators have tried to identify potential non-invasive markers for NASH diagnosis; however none of these markers have been externally validated(8-14). Validation and clinically availability of such a test would not only aid clinicians in the identification of patients with NASH, but also allow for non-invasive frequent monitoring of disease progression and response to therapy. Emerging data suggest that hepatocyte apoptosis, a highly organized and genetically controlled form of cell death, may play an important role in liver injury and disease progression in NAFLD (15, 16). Increase in hepatocyte cell death by apoptosis is typically present in humans with NASH as well as animal models of NASH but absent in those with NAFL (17). A central consequence of the apoptotic process is the activation of the effector caspases (mainly caspase 3) which cleave a number of different substrates inside the cell including Cytokeratin 18 (CK-18), the major intermediate filament protein in the liver, resulting in the characteristic morphologic changes of apoptosis (18). Recently in a “proof of concept” study, caspase generated CK-18 fragments were tested in the livers as well as in plasma of patients undergoing a liver biopsy for suspected NAFLD and healthy age-matched controls (19). CK-18 fragments were significantly elevated in the NAFLD patients as compared to controls and plasma levels correlated with the expression levels in the liver. Similar results were subsequently observed in an independent population of morbid obese patients undergoing bariatric surgery(20). The objective of the present study was to validate the clinical value of determination of the CK-18 fragment levels in blood for NASH diagnosis and assessment of disease severity in a large cohort of well characterized NAFLD patients from different regions across the United States.
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in vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease
Hepatology, 2006Co-Authors: Anna Wieckowska, Rocio A Lopez, Nizar N Zein, Arthur J Mccullough, Lisa Yerian, Ariel E FeldsteinAbstract:In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3– generated Cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma Cytokeratin-18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median [interquartile range]: 765.7 U/L [479.6-991.1], 202.4 U/L [160.4-258.2], 215.5 U/L [150.2-296.2], respectively; P < .001). Cytokeratin-18 fragment levels independently predicted NASH (OR 1.95; 95% CI 1.18-3.22; P .009 for every 50 U/L increase). A cutoff value of 395 U/L calculated using the receiver operating characteristic curve approach showed a specificity of 99.9%, a sensitivity of 85.7%, and positive and negative predictive values of 99.9% and 85.7%, respectively, for the diagnosis of NASH. In conclusion, these findings strongly suggest that determination of hepatocyte caspase activation in the blood is a strong and independent predictor of NASH in human subjects. These data highlight the potential usefulness of this test as a noninvasive diagnostic means of determining histological disease severity in patients with NAFLD. (HEPATOLOGY 2006;44:27-33.)
Martyna Kandefer-szerszeń - One of the best experts on this subject based on the ideXlab platform.
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Chemerin, retinol binding protein-4, Cytokeratin-18 and transgelin-2 presence in sera of patients with non-alcoholic liver fatty disease.
Annals of hepatology, 2016Co-Authors: Agnieszka Zwolak, Agnieszka Szuster-ciesielska, Jadwiga Daniluk, Justyna Semeniuk, Martyna Kandefer-szerszeńAbstract:Chemerin and retinol binding protein-4 (RBP-4) are adipokines which may play a role in the progression of NAFLD. It has been also suggested that Cytokeratin-18 (CK-18) could be a marker of hepatocyte caspase-directed death while transgelin-2 production could reflect stage of liver fibrosis. The aim of this study was to evaluate the level of the above adipokines in sera of patients with NAFLD and determine the relation between the level of transgelin-2 and fibrosis-4 index (FIB-4). Material and methods. Material and methods. Ninety-five subjects included initially to the study were divided into four groups: (I) prediabetics, obese with NAFLD and metabolic syndrome (MS), (II) lean with NAFLD and without MS, (III) obese without NAFLD and MS, and (IV) healthy individuals. We determined the levels of chemerin, RBP-4, transgelin-2 and CK-18 fragments in sera of patients with NAFLD. Moreover, we examined if the levels of CK-18 fragments and transgelin-2 correlates with FIB4 value. Results. Results. Chemerin and RBP-4 were highly expressed in Results. sera of all NAFLD, especially in obese individuals. Chemerin level was also linked to MS. High level of serum CK-18 fragments and transgelin-2 did not correlate with obesity and MS, but seemed to correlate with progression of NAFLD to liver fibrosis. Conclu- Conclusions. In sions. conclusion, the production of the two adipokines, chemerin and RBP-4, is strongly associated with obesity in patients with NAFLD. Serum concentrations of CK-18 fragments and transgelin-2 correlate with the severity of NAFLD, but not with obesity
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Chemerin, retinol binding protein-4, Cytokeratin-18 and transgelin-2 presence in sera of patients with non-alcoholic liver fatty disease
'Index Copernicus', 2016Co-Authors: Agnieszka Zwolak M.d., Agnieszka Szuster-ciesielska, Jadwiga Daniluk, Justyna Semeniuk, Martyna Kandefer-szerszeńAbstract:Background. Chemerin and retinol binding protein-4 (RBP-4) are adipokines which may play a role in the progression of NAFLD. It has been also suggested that Cytokeratin-18 (CK-18) could be a marker of hepatocyte caspase-directed death while transgelin-2 production could reflect stage of liver fibrosis. The aim of this study was to evaluate the level of the above adipokines in sera of patients with NAFLD and determine the relation between the level of transgelin-2 and fibrosis-4 index (FIB-4).Material and methods. Ninety-five subjects included initially to the study were divided into four groups: (I) prediabetics, obese with NAFLD and metabolic syndrome (Ms), (II) lean with NAFLD and without MS, (III) obese without NAFLD and MS, and (IV) healthy individuals. We determined the levels of chemerin, RBP-4, transgelin-2 and CK-18 fragments in sera of patients with NAFLD. Moreover, we examined if the levels of CK-18 fragments and transgelin-2 correlates with FIB4 value. Results. Chemerin and RBP-4 were highly expressed in sera of all NAFLD, especially in obese individuals. Chemerin level was also linked to MS. High level of serum CK-18 fragments and transgelin-2 did not correlate with obesity and MS, but seemed to correlate with progression of NAFLD to liver fibrosis.Conclusions. In conclusion, the production of the two adipokines, chemerin and RBP-4, is strongly associated with obesity in patients with NAFLD. Serum concentrations of CK-18 fragments and transgelin-2 correlate with the severity of NAFLD, but not with obesity
E Otero - One of the best experts on this subject based on the ideXlab platform.
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serum levels of Cytokeratin 18 tissue polypeptide specific antigen in liver diseases
Liver International, 2006Co-Authors: Arturo Gonzalezquintela, C Mella, Luisfernando Perez, Joaquin Campos, Nieves Mallo, Raimundo Lopezrodriguez, Santiago Tome, E OteroAbstract:: Objective: The tissue polypeptide-specific antigen (TPS, Cytokeratin-18, a normal constituent of the hepatocyte cytoskeleton) is a standard tumour marker. This study aimed to evaluate serum TPS levels in patients with liver disease. Methods: Serum TPS was measured with a commercial immunoassay in 884 individuals (753 outpatients from a liver disease clinic, 131 patients admitted to the hospital with acute liver disease). Results: Abnormally high (>80 U/l) TPS levels were found in 57.7% (95% CI 54.0–61.3%) of outpatients with liver disease. Elevated TPS levels were observed for all liver diseases, including fatty liver, alcoholic disease, chronic viral hepatitis, autoimmune hepatitis, cholestasis, transplantation, and hepatocarcinoma. TPS levels correlated with liver markers, particularly serum AST. In addition, TPS levels correlated with Knodell's score in patients with chronic hepatitis. TPS was increased in one-third of patients with normal liver enzyme values. Serum TPS levels decreased after specific therapy in patients with hepatitis C and autoimmune hepatitis. Abnormally high TPS levels were found in the vast majority of patients admitted to the hospital, with markedly high (>800 U/l) values being observed in 47.5% (95% CI 36.1–55.7%) of patients with alcoholic liver disease and in 80.8% (95% CI 60.0–92.7%) of patients with acute hepatitis. Conclusions: Serum TPS (Cytokeratin-18) is elevated in patients with non-malignant liver diseases, particularly in those with prominent cytolysis. Further studies are needed to evaluate the use of TPS as a marker of liver disease.
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serum Cytokeratins in alcoholic liver disease contrasting levels of Cytokeratin 18 and Cytokeratin 19
Alcohol, 2006Co-Authors: Arturo Gonzalezquintela, I Abdulkader, Luisfernando Perez, Joaquin Campos, E Otero, J Garcia, M R Alende, Santiago TomeAbstract:Abstract Serum Cytokeratin (CK) levels are widely used as tumor markers. Serum levels of CK-18, a tumor marker also known as tissue polypeptide specific antigen (TPS), are increased in patients with alcoholic liver disease. Cytokeratin-18 is the main component of Mallory bodies, a hallmark of alcoholic hepatitis, which may also contain CK-19. Serum levels of CK-18 and CK-19, a tumor marker also known as Cytokeratin FRAgment 21-1 (CYFRA 21-1) were investigated in (a) heavy drinkers with alcoholic liver disease ( n =15), (b) patients with malignancy ( n =22), and (c) healthy controls ( n =10). Serum levels of CYFRA 21-1 (CK-19) were markedly increased in patients with malignancy, but were similar in heavy drinkers and healthy controls. In contrast, serum levels of TPS (CK-18) in heavy drinkers were higher than those of healthy controls, and even tended to be higher than those of patients with malignancy. Both CK-19 and CK-18 levels were higher in cases of alcoholic hepatitis than in cases of fatty liver. Correlation with hepatocyte CK inclusions was stronger for serum TPS (CK-18) than for CYFRA 21-1 (CK-19). In conclusion, serum CYFRA 21-1 (CK-19) and TPS (CK-18) show a different pattern of increase that could reflect the composition of the altered hepatocyte CK network in alcoholic liver disease. Their usefulness as tumor markers, particularly that of serum TPS (CK-18), may be limited in patients with alcoholic liver disease.
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serum levels of tissue polypeptide specific antigen are correlated with hepatocyte Cytokeratin expression in alcoholic liver disease
Alcoholism: Clinical and Experimental Research, 2004Co-Authors: Arturo Gonzalezquintela, C Mella, I Abdulkader, Luisfernando Perez, Joaquin Campos, E Otero, J FortezaAbstract:Background: Serum levels of the tumor marker tissue polypeptide specific antigen (TPS, Cytokeratin 18 fragments) are increased in patients with alcoholic liver disease, particularly in cases of alcoholic hepatitis. Mallory bodies, characteristic of alcoholic hepatitis, are Cytokeratin 8 and 18 aggregates. The study was aimed at investigating the possible relationship of serum TPS levels with hepatocyte Cytokeratin expression in patients with alcoholic liver disease. Methods: Twenty-four patients with alcoholic liver disease were studied. Immunohistochemical staining for Cytokeratins 8 and 18 was performed in liver specimens by means of CAM 5.2 monoclonal antibody. The number of hepatocytes containing CAM 5.2-reactive Cytokeratin inclusions was compared with serum TPS levels. Main Results and Conclusions: The vast majority of alcoholics (95%) showed increased (>100 units/liter) serum TPS levels. Serum TPS levels were significantly correlated with the number of hepatocyte Cytokeratin inclusions. Serum TPS levels can predict hepatocyte Cytokeratin expression in patients with alcoholic liver disease.
Arturo Gonzalezquintela - One of the best experts on this subject based on the ideXlab platform.
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serum levels of Cytokeratin 18 tissue polypeptide specific antigen in liver diseases
Liver International, 2006Co-Authors: Arturo Gonzalezquintela, C Mella, Luisfernando Perez, Joaquin Campos, Nieves Mallo, Raimundo Lopezrodriguez, Santiago Tome, E OteroAbstract:: Objective: The tissue polypeptide-specific antigen (TPS, Cytokeratin-18, a normal constituent of the hepatocyte cytoskeleton) is a standard tumour marker. This study aimed to evaluate serum TPS levels in patients with liver disease. Methods: Serum TPS was measured with a commercial immunoassay in 884 individuals (753 outpatients from a liver disease clinic, 131 patients admitted to the hospital with acute liver disease). Results: Abnormally high (>80 U/l) TPS levels were found in 57.7% (95% CI 54.0–61.3%) of outpatients with liver disease. Elevated TPS levels were observed for all liver diseases, including fatty liver, alcoholic disease, chronic viral hepatitis, autoimmune hepatitis, cholestasis, transplantation, and hepatocarcinoma. TPS levels correlated with liver markers, particularly serum AST. In addition, TPS levels correlated with Knodell's score in patients with chronic hepatitis. TPS was increased in one-third of patients with normal liver enzyme values. Serum TPS levels decreased after specific therapy in patients with hepatitis C and autoimmune hepatitis. Abnormally high TPS levels were found in the vast majority of patients admitted to the hospital, with markedly high (>800 U/l) values being observed in 47.5% (95% CI 36.1–55.7%) of patients with alcoholic liver disease and in 80.8% (95% CI 60.0–92.7%) of patients with acute hepatitis. Conclusions: Serum TPS (Cytokeratin-18) is elevated in patients with non-malignant liver diseases, particularly in those with prominent cytolysis. Further studies are needed to evaluate the use of TPS as a marker of liver disease.
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serum Cytokeratins in alcoholic liver disease contrasting levels of Cytokeratin 18 and Cytokeratin 19
Alcohol, 2006Co-Authors: Arturo Gonzalezquintela, I Abdulkader, Luisfernando Perez, Joaquin Campos, E Otero, J Garcia, M R Alende, Santiago TomeAbstract:Abstract Serum Cytokeratin (CK) levels are widely used as tumor markers. Serum levels of CK-18, a tumor marker also known as tissue polypeptide specific antigen (TPS), are increased in patients with alcoholic liver disease. Cytokeratin-18 is the main component of Mallory bodies, a hallmark of alcoholic hepatitis, which may also contain CK-19. Serum levels of CK-18 and CK-19, a tumor marker also known as Cytokeratin FRAgment 21-1 (CYFRA 21-1) were investigated in (a) heavy drinkers with alcoholic liver disease ( n =15), (b) patients with malignancy ( n =22), and (c) healthy controls ( n =10). Serum levels of CYFRA 21-1 (CK-19) were markedly increased in patients with malignancy, but were similar in heavy drinkers and healthy controls. In contrast, serum levels of TPS (CK-18) in heavy drinkers were higher than those of healthy controls, and even tended to be higher than those of patients with malignancy. Both CK-19 and CK-18 levels were higher in cases of alcoholic hepatitis than in cases of fatty liver. Correlation with hepatocyte CK inclusions was stronger for serum TPS (CK-18) than for CYFRA 21-1 (CK-19). In conclusion, serum CYFRA 21-1 (CK-19) and TPS (CK-18) show a different pattern of increase that could reflect the composition of the altered hepatocyte CK network in alcoholic liver disease. Their usefulness as tumor markers, particularly that of serum TPS (CK-18), may be limited in patients with alcoholic liver disease.
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serum levels of tissue polypeptide specific antigen are correlated with hepatocyte Cytokeratin expression in alcoholic liver disease
Alcoholism: Clinical and Experimental Research, 2004Co-Authors: Arturo Gonzalezquintela, C Mella, I Abdulkader, Luisfernando Perez, Joaquin Campos, E Otero, J FortezaAbstract:Background: Serum levels of the tumor marker tissue polypeptide specific antigen (TPS, Cytokeratin 18 fragments) are increased in patients with alcoholic liver disease, particularly in cases of alcoholic hepatitis. Mallory bodies, characteristic of alcoholic hepatitis, are Cytokeratin 8 and 18 aggregates. The study was aimed at investigating the possible relationship of serum TPS levels with hepatocyte Cytokeratin expression in patients with alcoholic liver disease. Methods: Twenty-four patients with alcoholic liver disease were studied. Immunohistochemical staining for Cytokeratins 8 and 18 was performed in liver specimens by means of CAM 5.2 monoclonal antibody. The number of hepatocytes containing CAM 5.2-reactive Cytokeratin inclusions was compared with serum TPS levels. Main Results and Conclusions: The vast majority of alcoholics (95%) showed increased (>100 units/liter) serum TPS levels. Serum TPS levels were significantly correlated with the number of hepatocyte Cytokeratin inclusions. Serum TPS levels can predict hepatocyte Cytokeratin expression in patients with alcoholic liver disease.
Naim Alkhouri - One of the best experts on this subject based on the ideXlab platform.
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plasma Cytokeratin 18 level as a novel biomarker for liver fibrosis in children with nonalcoholic fatty liver disease
Journal of Pediatric Gastroenterology and Nutrition, 2016Co-Authors: Chetan Mandelia, Valerio Nobili, Elizabeth Collyer, Sana Mansoor, Rocio Lopez, Sara Lappe, Naim AlkhouriAbstract:ABSTRACTObjectives:Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity epidemic and affects approximately 10% of children in the US. The presence of hepatic fibrosis may be the most important factor in determining the prognosis of NAFLD. Noninvasive methods to identi
